Synergistic impact of CAG intermediate alleles in the HTT gene and microRNA dysregulation exacerbates spliceosome impairment and accelerates Tau pathology in the caudate nucleus of late-onset Alzheimer's disease

BackgroundLate-onset Alzheimers disease (LOAD) accounts for more than 95% of AD cases. Previously, we have described that 6% of AD patients present CAG intermediate alleles in the huntingtin gene (HTT IAs). The caudate nucleus, the most affected region in Huntingtons disease, is highly sensitive to these HTT CAG expansions, as they can induce epigenetic changes, including altered microRNA profiles. All this implies a potential source of gene expression deregulation, affecting disease onset and/or progression in LOAD patients with HTT IAs. MethodsWe genotyped HTT CAG repeats and Apolipoprotein E (APOE) in postmortem brain frozen samples from 323 LOAD patients and 335 healthy controls. From them, we selected caudate samples of HTT IA carrier and non-carrier LOAD patients and controls, with neuropathological study, and performed next-generation microRNA sequencing, in silico target prediction and pathway analysis, followed by molecular and histopathological studies. ResultsOur study revealed that the presence of HTT IAs decreases survival in LOAD patients after disease onset. MicroRNA profiles in the caudate nucleus are altered in all LOAD compared to the control cases but are more pronounced in HTT IAs carriers. In silico analysis suggests that the microRNAs expressed differentially in HTT IAs carriers regulate key components of the spliceosome, affecting splicing factors of the SRSF family or the nuclear FUS-SFPQ complex, which was confirmed by different techniques. This leads to an increase in Tau 3R protein, conducting to a higher presence of ghost tangles, the last state of neurofibrillary tangles, in LOAD patients with HTT IAs. In addition, they also present a higher number of HTT-positive neurons in a CAG repeat expansion-dependent manner. ConclusionsOur findings demonstrate a synergistic effect of HTT IAs and miRNAs deregulation in the evolution of tau pathology, which could be related to an accelerated misprocessing and subsequent aggregation of the Tau 3R isoform, favoring a subsequent faster disease progression. The incorporation of genetic screening for HTT alleles into clinical practice would allow a more accurate classification of LOAD patients, facilitating the design of personalized therapeutic interventions and improving the prospects for the management of this debilitating disease.